There are thousands of rare genetic diseases that have no approved treatment. Recursion Pharmaceuticals has developed a drug discovery platform that seeks to re-purpose known drugs for the treatment of such diseases. The platform consists of high content immunofluorescent image analysis and transcellular resistance measurements. These measurements evaluated using machine-learning algorithms to identify relevant and on- target changes induced by both RNAi and various chemicals. These assays can be simultaneously performed on thousands of rare genetic disease models. In this grant, we specifically propose to: Model 2,000 genetic diseases in multiple human cell types using RNAi technology. Identify and prioritize 200 of these disease models with the most compelling phenotypic changes, according to multi-parametric quantification. Utilize these 200 disease models as the basis of chemical suppressor screens of thousands of known drug candidates. Validate the 20 best drug/disease combinations using an orthogonal genetic manipulation technique in human cells. Study the best five to ten validated drug/disease combinations in relevant animal models. The proposed study would have significant societal and commercial implications.